Antimicrobial effect of oral care gel containing hinokitiol and 4-isopropyl-3-methylphenol against intraoral pathogenic microorganisms.
Deterioration of oral hygiene is closely related to an increase in severity and mortality of corona virus disease-19 (COVID-19), and also contributes to the development of various diseases such as aspiration pneumonia or Alzheimer's. Oral care is attracting high interest in Japan, which has entered a super-aging society. In this study, we aimed to investigate whether commercially available Hinora® (HO), an oral care gel containing hinokitiol and 4-isopropyl-3-methylphenol (IPMP), has biofilm formation inhibitory and antimicrobial activities against various intraoral pathogen microorganisms. Candida species, Aggregatibacter actinomycetemcomitans, Staphylococcus aureus, and Pseudomonas aeruginosa were selected during the study period, all of which were analyzed using antimicrobial disc, microorganism turbidity, and crystal violet assays. In addition, the germ tube test using Candida albicans (C. albicans) was performed with a modification of Mackenzie's method. Images for morphological observation of the germ tubes were acquired using an inverted microscope. For comparison between products, we used Refrecare® (RC), which only contains hinokitiol (not containing IPMP). All the intraoral pathogenic microorganisms showed drug susceptibility against undiluted forms of HO and/or RC. In particular, HO was more effective at lower concentrations than RC. In the HO-added group, inhibition circles were observed in all bacteria except P. aeruginosa when added at a concentration of 0.5 g/mL or more. The optical density values at 590 nm (crystal violet) and/or 600 nm (microorganism turbidity) of all the fungi and bacteria were significantly lower when cultured in medium with HO. Inhibition of growth or biofilm formation was observed when HO was added at a concentration of 0.05 g/mL or higher. To investigate the action mechanism of HO, germ tube tests were performed in C. albicans. The results showed that culturing C. albicans in soybean-casein digest broth with HO (0.05 g/mL) significantly suppressed germ tube formation. These data suggest that oral care gel-containing hinokitiol and IPMP has strong biofilm formation inhibitory activity, as well as antifungal and antimicrobial effects against Candida fungi and multiple intraoral pathogenic microorganisms. Therefore, it may be a promising treatment option for oral infections.


Investigating the susceptibility of treatment-resistant oesophageal tumours to natural killer cell-mediated responses.
The majority of oesophageal adenocarcinoma (OAC) patients do not respond to multimodal treatment regimens and face dismal survival rates. Natural killer (NK) cells are crucial anti-tumour immune cells, and this study investigated the susceptibility of treatment-resistant OAC cells to these potent tumour killers. Natural killer receptor (NKR) ligand expression by OE33CisP (cisplatin-sensitive) and OE33CisR (cisplatin-resistant) cells was investigated. The immunomodulatory effects of OE33CisP and OE33CisR cells on NK cell phenotype and function were assessed. Finally, the impact of chemotherapy regimens on NKR ligand shedding was examined. Our data revealed significantly less surface expression of activating ligands B7-H6, MICA/B, ULBP-3 and activating/inhibitory ligands PVRL-1 and PVRL-4 by OE33CisR cells, compared to OE33CisP cells. Co-culture with OE33CisR cells reduced the frequencies of NKp30+ and NKp46+ NK cells and increased frequencies of TIGIT+, FasL+ and TRAIL+ NK cells. Frequencies of IFN-γ-producing NK cells increased while frequencies of TIM-3+ NK cells decreased after culture with OE33CisP and OE33CisR cells. Frequencies of circulating NKp30+ NK cells were significantly lower in OAC patients with the poorest treatment response and in patients who received FLOT chemotherapy, while B7-H6 shedding by OAC tumour cells was induced by FLOT. Overall, OE33CisR cells express less activating NKR ligands than OE33CisP cells and have differential effects on NKR expression by NK cells. However, neither cell line significantly dampened NK cell cytokine production, death receptor expression or degranulation. In addition, our data indicate that FLOT chemotherapy may promote B7-H6 shedding and immune evasion with detrimental consequences in OAC patients.


Single-Molecule Fluorescence Imaging Reveals GABAB Receptor Aggregation State Changes.
The GABAB receptor is a typical G protein-coupled receptor, and its functional impairment is related to a variety of diseases. While the premise of GABAB receptor activation is the formation of heterodimers, the receptor also forms a tetramer on the cell membrane. Thus, it is important to study the effect of the GABAB receptor aggregation state on its activation and signaling. In this study, we have applied single-molecule photobleaching step counting and single-molecule tracking methods to investigate the formation and change of GABAB dimers and tetramers. A single-molecule stoichiometry assay of the wild-type and mutant receptors revealed the key sites on the interface of ligand-binding domains of the receptor for its dimerization. Moreover, we found that the receptor showed different aggregation behaviors at different conditions. Our results offered new evidence for a better understanding of the molecular basis for GABAB receptor aggregation and activation.


Quantitative Sensory Testing and Current Perception Threshold Testing in Patients With Chronic Pain Following Lower Extremity Fracture.
Chronic pain is a significant problem for patients with lower extremity injuries. While pain hypersensitivity has been identified in many chronic pain conditions, it is not known whether patients with chronic pain following lower extremity fracture report pain hypersensitivity in the injured leg. To quantify and compare peripheral somatosensory function and sensory nerve activation thresholds in persons with chronic pain following lower extremity fractures with a cohort of persons with no history of lower extremity fractures. This was a cross-sectional study where quantitative sensory testing and current perception threshold testing were conducted on the injured and noninjured legs of cases and both legs of controls. A total of 14 cases and 28 controls participated in the study. Mean time since injury at the time of testing for cases was 22.3 (standard deviation = 12.1) months. The warmth detection threshold ( p = .024) and nerve activation thresholds at 2,000 Hz ( p < .001) and 250 Hz ( p = .002), respectively, were significantly higher in cases compared to controls. This study suggests that patients with chronic pain following lower extremity fractures may experience hypoesthesia in the injured leg, which contrasts with the finding of hyperesthesia previously observed in other chronic pain conditions but is in accord with patients with nerve injuries and surgeries. This is the first study to examine peripheral sensory nerve function at the site of injury in patients with chronic pain following lower extremity fractures using quantitative sensory testing and current perception threshold testing.


Property of kinin-forming enzyme in rat stomach.
The effects of inhibitors on the kinin-forming enzyme (KFE) activity in the rat stomach were investigated at pH 4.8. The KFE activity was unaffected by trasylol (200 KIU/ml), soybean trypsin inhibitor (100 microgram/ml) and p-tosyl-L-lysine-chloromethyl ketone (10-3 M), but was inhibited by pepstatin A (10(-6) M) and chymostatin (1.5 x 10(-4) M). Each product from the rat plasma kininogen by the rat stomach KFE and the bovine spleen cathepsin D was eluated at the same retention time on the equilibrium chromatography on the SP-Sephadex C-25 column. The KFE activity in the rat stomach was considerably high compared with that in various regions of the intestine. These results suggest that the KFE is characteristically similar to cathepsin D, and the enzyme is probably relevant to the function of the stomach.


A novel mutation of the epsilon-sarcoglycan gene in a Chinese family with myoclonus-dystonia syndrome.
In a Chinese myoclonus-dystonia syndrome (MDS) family presented with a phenotype including a typical MDS, cervical dystonia, and writer's cramp, genetic analyses revealed a novel 662 + 1insG heterozygous mutation in exon 5 in the epsilon-sarcoglycan (SGCE) gene, leading to a frameshift with a down stream stop codon. Low SGCE mRNA levels were detected in the mutation carriers by real-time PCR, suggesting that the nonsense mutation might interfere with the stability of SGCE mRNA. This is the first report on Chinese with a SGCE mutation leading to MDS. Our data support the fact that same mutation of SGCE gene can lead to a varied phenotype, even in the same family.


Episodic exposures to chemicals: what relevance to chemical intolerance?
Episodic exposures refer to intermittent acute exposures to chemicals that ordinarily have a rapid onset and short duration of effect. There has been a long tradition in preclinical behavioral pharmacology of using episodic-exposure paradigms in order to establish dose-response functions in individual organisms. In these experiments, stable baselines of behavior are first established and then followed by administering varying doses of a drug intermittently, for example, once or twice a week. The power of this approach is well established; the within-subjects design reduces error variance, allows exploration of the entire range of effective doses, and can be used to identify individual differences in drug sensitivity. Of course, the approach is only applicable to reversibly acting compounds, and checks need to be included to insure effects of one dose are not influenced by prior exposure to another dose. We have used baseline approaches to evaluate the effects of pesticides and solvents on the behavior of adult male rats and mice. Moreover, a novel probabilistic dose-tolerance analysis applied to the data suggests substantial individual differences in chemical sensitivity, often spanning orders of magnitude. These results suggest that individual differences in chemical sensitivity may be much greater than previously acknowledged.


Echocardiographic recognition of silent aortic root dilatation in Marfan's syndrome.
Echocardiography has proven a useful and sensitive means to determine noninvasively the cardiac dimensions. This report describes the echocardiographic detection of progressive dilatation of the aortic root over an 18-month period, which led to death in a 33-year-old man with Marfan's syndrome; however, at no time was the aortic dilatation evident on chest x-ray films. This patient illustrates the sensitivity of the echocardiogram in detecting and assessing the severity of disease of the aortic root not readily assessed by other noninvasive techniques and the value of serial measurements of aortic dimensions in patients with proven or suspected dilatation of the aortic root.


Illuminating Music: Impact of Color Hue for Background Lighting on Emotional Arousal in Piano Performance Videos.
This study sought to determine if hues overlayed on a video recording of a piano performance would systematically influence perception of its emotional arousal level. The hues were artificially added to a series of four short video excerpts of different performances using video editing software. Over two experiments 106 participants were sorted into 4 conditions, with each viewing different combinations of musical excerpts (two excerpts with nominally high arousal and two excerpts with nominally low arousal) and hue (red or blue) combinations. Participants rated the emotional arousal depicted by each excerpt. Results indicated that the overall arousal ratings were consistent with the nominal arousal of the selected excerpts. However, hues added to video produced no significant effect on arousal ratings, contrary to predictions. This could be due to the domination of the combined effects of other channels of information (e.g., the music and player movement) over the emotional effects of the hypothesized influence of hue on perceived performance (red expected to enhance and blue to reduce arousal of the performance). To our knowledge this is the first study to investigate the impact of these hues upon perceived arousal of music performance, and has implications for musical performers and stage lighting. Further research that investigates reactions during live performance and manipulation of a wider range of lighting hues, saturation and brightness levels, and editing techniques, is recommended to further scrutinize the veracity of the findings.


Primary signet ring cell carcinoma with tubular adenoma of the rectum: A case report and a review of the literature.
Among the various forms of colorectal carcinomas, primary signet ring cell carcinoma (SRCC) of rectum is infrequent. Primary SRCC with adenoma is even rarer. Due to its low morbidity and lack of obvious manifestations at early stages, it is difficult to make an early diagnosis and perform surgical intervention in time. Herein, we reported a case of primary SRCC with tubular adenoma of rectum and also performed a review of the literature of such cases, in hopes of expanding the general understanding regarding such cases. A 61-year-old male patient presented with rectal bleeding for 1 week. A neoplasm could be palpated through a rectal examination, with a size of 4.0 cm by 3.0 cm, at a distance of 5 cm from the anal edge. Magnetic resonance imaging examination and colonoscopies were performed to confirm the finding, and 4 tissue specimens were obtained for histopathologic biopsy. The result of biopsy was high-grade intraepithelial neoplasia with an adenoma component. Surgical resection was performed, and histopathologic and immunohistochemical staining examination of the resection confirmed the diagnosis of SRCC with tubular adenoma. The patient was discharged from hospital 12 days postsurgery, without any complications. Further chemotherapy and supportive treatments were suggested to him and will be followed at a local hospital. Primary rectal SRCC has a rather low morbidity. Furthermore, a rectal SRCC with adenoma which was presenting in this case is even more rare. Besides lack of clinical characters, delay of diagnosis and treatment frequently occur. So far, a surgical procedure has still been one of the most effective treatments. Considering of metastasis and the poor prognosis, early diagnosis, in-time radical resection, and a comprehensive followed treatment are recommended for a higher 5-year overall survival.


Environmental neurotoxic illness: research for prevention.
Recognition of the deleterious neurological effects of chemicals has evolved from anecdotal observation to studies of illness in persons exposed to high doses. Now, the more subtle effects of exposures to environmental neurotoxicants are being documented: reduction in intelligence, impairment in reasoning ability, shortening of attention span, and alteration of behavior. Substances to which millions of persons are exposed occupationally and in the general environment that can result in such deficits include lead, organophosphorus pesticides, certain chlorinated hydrocarbons, carbon disulfide, solvents, and mercury. The first step in the prevention of neurological impairments due to environmental exposures is to assess the toxicity of chemicals. Fewer than 10% of the 70,000 chemicals in commercial use have been evaluated for neurotoxicity. This knowledge gap needs to be narrowed by building on existing systems of toxicity testing. Concurrent with assessment of chemicals will be tiers of in vivo screening tests to measure functional and structural changes following exposures in vitro. Epidemiologic surveillance of populations at high risk will continue to inform on the ranking of suspect or known neurotoxicants. Research and researchers must become more sophisticated in the development and application of refined biologic markers so the findings can be used to detect absorption of toxicants and early neurological or neurobehavioral dysfunction before disability occurs and to protect human health and the environment.


Human polymorphonuclear leukocyte interaction with cyclosporine A.
The effects of cyclosporin A (cyA) on human polymorphonuclear leukocyte function, including phagocytosis, its associated metabolic burst, bacterial killing, and chemotaxis, were evaluated. Both Pseudomonas aeruginosa and Staphylococcus aureus were used as test particles. Polymorphonuclear leukocytes incubated in 10 and 50 micrograms of cyA per ml behaved normally with respect to phagocytosis and hexose monophosphate shunt activity at both high (10:1) and low (2:1) S. aureus/leukocyte ratios. With a small bacterial inoculum, killing of S. aureus was slightly impaired at early times only in the presence of 50 micrograms of cyA per ml. Phagocytosis and killing of P. aeruginosa with both large and small bacterial inocula were unaffected by cyA. Chemotaxis was within normal limits under all conditions. In addition, polymorphonuclear leukocytes from four renal transplant recipients receiving both cyA and prednisone demonstrated normal metabolic bursts and bacterial killing with both small and large inocula of S. aureus.


Immunogenic Chemotherapy Sensitizes Renal Cancer to Immune Checkpoint Blockade Therapy in Preclinical Models.
BACKGROUND Renal cell carcinoma (RCC) is among the most common malignant cancers of males worldwide. For advanced RCC patients, there still is no effective therapy. Immune checkpoint blockade therapies have shown benefits for many cancers, but previous clinical trials of immune checkpoint blockade therapies in RCC patients achieved only modest results. MATERIAL AND METHODS We explored the effects of combining chemotherapy with immune checkpoint blockade therapy in RCC xenograft mouse models. We also studied the potential mechanisms by which chemotherapy might enhance the efficacy of immune checkpoint blockade therapy, both in vitro and in vivo. RESULTS Our results showed that many commonly used chemotherapy agents can induce immunogenic marker release in RCC cell lines. Importantly, the RCC xenograft mouse model mice who received the combination treatment of 5-fluorouracil (5-FU) and anti-programmed cell death-ligand 1 (PD-L1) antibodies (Abs) had longer survival times compared to those who received 5-FU or anti-PD-L1 Abs alone. Also, increased key cytokines that promote tumor immunity, such as IL-2, IFN-γ, and TNF-α, as well as tumor-infiltrating cytotoxic T cells, were also increased after the combination treatment. CONCLUSIONS We conclude that 5-FU can sensitize RCC to anti-PD-L1 treatment by releasing the immune suppression in the tumor microenvironment.


Prescription Opioid Misuse After a Recent Sexual Assault: A Randomized Clinical Trial of a Video Intervention.
Prescription opioid (PO) misuse is increasing and is associated with overdose. Individuals who experienced a recent sexual assault are at risk for increased substance use, yet limited interventions target PO misuse after sexual assault. The current study examined the efficacy of video interventions on PO misuse after sexual assault. Adolescent girls and women (n = 154) were recruited in the context of a sexual assault medical forensic exam in the emergency department. Effects of a prevention of post-rape stress (PPRS) video and a pleasant imagery and relaxation instruction (PIRI) video were compared with treatment as usual (TAU) during a sexual assault medical forensic exam on PO misuse. Participants reported if they had used POs for non-medical purposes since the sexual assault at 1.5 month follow-up. Results from a logistic regression analysis indicated that participants with a prior sexual assault were less likely to misuse prescription opioids 1.5 months after the assault in the PIRI condition compared with TAU. There were no main effects for video condition and no interactions for the PPRS condition on PO misuse. Providing the PIRI video, or teaching other types of mindfulness or relaxation exercises, may be warranted as a secondary prevention for individuals during the sexual assault medical forensic exam for those with a prior sexual assault history. This research provides an initial examination of the impact of mindfulness skills recently after traumatic event exposure on PO misuse. (Am J Addict 2019;28:376-381).


Distribution of pleural injectate. Effect of volume of injectate and animal rotation.
It is controversial whether rotation is necessary for patients undergoing pleurodesis. In addition, the optimal volume of the injectate remains to be determined. The purpose of this study was to determine the importance of rotation and the volume of the agent on the intrapleural dispersion of agents injected into the pleural space of rabbits. Technetium 99m pertechnetate (99mTc) in 0.5, 1.0, or 2.0 ml of saline solution was injected into ten lightly anesthetized rabbits, half of whom were rotated for 1 min after the injection. Static images were obtained in the anterior projection 1 and 5 min after the injection. After the second scan, the limits of the lung were defined by obtaining a perfusion scan immediately after the intravenous injection of macroaggregates of 99mTc-labeled serum albumin. The degree of dispersion was significantly greater in the nonrotated groups both at 1 min (F = 8.11, p = 0.0085) and at 5 min (F = 5.89, p = 0.0274). In addition, the homogeneity of the distribution of the injectate was not improved with rotation. From this study, we conclude that rotation of the animal for 1 min after the intrapleural injection does not improve the distribution of the injectate throughout the pleural space. Furthermore, a volume of 0.5 ml is sufficient for all pleural surfaces to be exposed.


Connecting the Dots: From Skin Barrier Dysfunction to Allergic Sensitization, and the Role of Moisturizers in Repairing the Skin Barrier
The skin is one of the largest immunologic organs in the body and a continuous target for allergic and immunologic responses. Impairment of the skin barrier increases the likelihood of external antigens and pathogens entering and creating inflammation, which can potentially lead to skin infections, allergies, and chronic inflammatory diseases such as atopic and contact dermatitis. Functionally, the skin barrier can be divided into four different levels. From outermost to innermost, these highly interdependent levels are the microbiome, chemical, physical, and immune levels. The objective of this review is to provide an update on current knowledge about the relationship between skin barrier function and how dysfunction at each level of the skin barrier can lead to allergic sensitization, contact dermatitis, and the atopic march, and examine how to best repair and maintain this barrier through the use of moisturizers. J Drugs Dermatol. 2019;18(6):581-586.


Can the unauthorised use of ceftiofur be detected in poultry?
Ceftiofur is a third-generation cephalosporin antibiotic used to treat cattle and swine for bacterial infection of the respiratory tract. It is not authorised for use in poultry within the European Union. Due to the complexity of the chemistry and metabolism of ceftiofur, maximum residue limits (MRLs) are based on desfuroylceftiofur (DFC) equivalents after chemical conversion of all compounds that have an intact ß-lactam ring. In practice the DFC is usually stabilised as the acetamide (desfuroylceftiofur acetamide - DFCA) for analysis. Because of recent evidence of off-label use in the European Union, a policy need emerged to develop a cost-effective method for the detection of ceftiofur residues in poultry tissues. One-day-old chicks were each dosed subcutaneously with ceftiofur and samples taken from day 1 to day 44 post-dosing. Residues of ceftiofur parent compound were detected in whole chicks, wing feathers and faeces. On the basis of this finding it was decided to evaluate ceftiofur parent, as the marker, instead of proceeding with the time-consuming conversion to DFCA. Expected metabolites, DFC and desfuroylceftiofur cysteine disulfide (DCCD), were not detected in whole chicks, muscle or liver, but DFC was found in wing feathers. These results indicate that determination of ceftiofur parent compound in either whole chicks or possibly wing feathers and faeces may allow the detection of the misuse of ceftiofur.


Serological Evidence of Chikungunya Virus among Acute Febrile Patients in Southern Mozambique.
In the last two decades, chikungunya virus (CHIKV) has rapidly expanded to several geographical areas, causing frequent outbreaks in sub-Saharan Africa, South East Asia, South America, and Europe. Therefore, the disease remains heavily neglected in Mozambique, and no recent study has been conducted. Between January and September 2013, acute febrile patients with no other evident cause of fever and attending a health center in a suburban area of Maputo city, Mozambique, were consecutively invited to participate. Paired acute and convalescent serum samples were requested from each participant. Convalescent samples were initially screened for anti-CHIKV IgG using a commercial indirect immunofluorescence test, and if positive, the corresponding acute sample was screened using the same test. Four hundred patients were enrolled. The median age of study participants was 26 years (IQR: 21-33 years) and 57.5% (224/391) were female. Paired blood samples were obtained from 209 patients, of which 26.4% (55/208) were presented anti-CHIKV IgG antibodies in the convalescent sample. Seroconversion or a four-fold titer rise was confirmed in 9 (4.3%) patients. The results of this study strongly suggest that CHIKV is circulating in southern Mozambique. We recommend that CHIKV should be considered in the differential diagnosis of acute febrile illness in Mozambique and that systematic surveillance for CHIKV should be implemented.


Differential diagnostics of interstitial lung diseases.
Interstitial lung diseases very often do not only affect the lung tissue, but are part of multisystem diseases. Awareness of their classification and differential diagnosis therefore does not belong only to respiratory departments, but shall be acknowledged by all specialisations. It is obvious that the approach to a patient with life-threatening disease or acute onset of symptoms differently then patients with slow disease onset or "accidentally" detected lung abnormalities. The presented manuscript brings a differential diagnostic approach to facilitate orientation in the field of interstitial ling diseases.


Effects of fractionated irradiation on the cytoskeleton and basal lamina in parotid glands--an immunohistochemical study.
Cytoskeletal, cytocontractile and basement membrane proteins were studied using the immunofluorescence technique in the parotid gland in female rats after half-side fractionated megavoltage irradiation. The non-irradiated parallel-handled parotid glands served as controls. The qualitative expression of cytoskeletal proteins remained unchanged 10 days following irradiation compared to controls, i.e. cytokeratin was observed but not vimentin, desmin or GFAP (glial fibrillary acidic proteins). Six months after irradiation the cytokeratin expression adjacent to duct lumina was clearly stronger. Actin staining was more pronounced in the periphery of the acini. Ten days after irradiation no alterations of the basal lamina proteins, laminin and fibronectin, were detected. Six months post-irradiation laminin deposits were detected in areas where the entire acini had degenerated and had been replaced by fibrosis. An increased expression of fibronectin was also observed in the stroma at that time, reflecting an increased fibrosis. In areas where the acini remained, laminin immunofluorescence was mainly found in basal laminae of normal thickness, but the mean diameter of the acini seemed to have increased. This indicates a regeneration of acini and a restructuring of the basal lamina of the parenchyma.


Peptide internalization enabled by folding: triple helical cell-penetrating peptides.
Cell-penetrating peptides (CPPs) are known as efficient transporters of molecular cargo across cellular membranes. Their properties make them ideal candidates for in vivo applications. However, challenges in the development of effective CPPs still exist: CPPs are often fast degraded by proteases and large concentration of CPPs required for cargo transporting can cause cytotoxicity. It was previously shown that restricting peptide flexibility can improve peptide stability against enzymatic degradation and limiting length of CPP peptide can lower cytotoxic effects. Here, we present peptides (30-mers) that efficiently penetrate cellular membranes by combining very short CPP sequences and collagen-like folding domains. The CPP domains are hexa-arginine (R6) or arginine/glycine (RRGRRG). Folding is achieved through multiple proline-hydroxyproline-glycine (POG [proline-hydroxyproline-glycine])n repeats that form a collagen-like triple helical conformation. The folded peptides with CPP domains are efficiently internalized, show stability against enzymatic degradation in human serum and have minimal toxicity. Peptides lacking correct folding (random coil) or CPP domains are unable to cross cellular membranes. These features make triple helical cell-penetrating peptides promising candidates for efficient transporters of molecular cargo across cellular membranes.


Postsynaptic alpha 1- and alpha 2-adrenoceptors in human blood vessels: interactions with exogenous and endogenous catecholamines.
The relative efficacy of epinephrine and norepinephrine on vascular alpha 1- and alpha 2-adrenoceptors and also the difference in vasoconstriction induced by exogenous norepinephrine as opposed to neuronally released norepinephrine were studied in the forearm of healthy volunteers. Intra-arterial cumulative dose infusions of epinephrine and norepinephrine (0.6, 1.6 and 4.0 ng kg-1 min-1) were given in the presence of saline, the selective alpha 1-antagonist doxazosin (0.1 microgram kg min-1) the selective alpha 2-antagonist yohimbine (1.0 microgram kg min-1) and the combination of both antagonists. beta-Adrenoceptor-mediated effects were prevented by a concomitant i.a. infusion of propranolol (1.0 microgram kg-1 min-1). Forearm blood flow (FBF) was measured before each infusion and at the end of each dose step. Neuronal norepinephrine was released by i.a. infusion of tyramine in three cumulative doses (0.25, 0.50 and 1.25 micrograms kg-1 min-1) and by lower body negative pressure (LBNP, -40 mmHg for 5 min). Changes in FBF were measured without and with concomitant i.a. infusions of the aforementioned doses of doxazosin and yohimbine. In the LBNP experiment the opposite arm was used as a control. Forearm blood flow was measured by plethysmography. Epinephrine and norepinephrine induced an equal and dose-dependent vasoconstriction, which was significantly inhibited by doxazosin as well as yohimbine and to a greater extent by the combination of the antagonists. No differences were found between epinephrine and norepinephrine in this respect.(ABSTRACT TRUNCATED AT 250 WORDS)


Intravenous indomethacin and changes of renal function in premature infants with patent ductus arteriosus.
Selected parameters of renal function were studied in premature infants with a significant patent ductus arteriosus who were treated with intravenous indomethacin according to a specific protocol. Urine volume, glomerular filtration rate, urine sodium, and the fractional excretion of sodium were analyzed in 17; osmolar, sodium, and free water clearances in 8; and indomethacin pharmacokinetics in 7 premature infants. All renal function parameters analyzed decreased during indomethacin therapy: urine volume and glomerular filtration rate returned to normal, while urine sodium, fractional excretion of sodium, and the osmolar, sodium, and free water clearances remained low 24 hours after cessation of therapy. The water retention, shown by the reduced free water clearance, had no apparent deleterious effects, probably because of the infants' low fluid intake. Indomethacin pharmacokinetic parameters (clearance, area under the curve) may account in part for the variability of the fractional excretion of sodium, glomerular filtration, and urine flow rate.


Novel imaging phenotypes of naïve asthma patients with distinctive clinical characteristics and T2 inflammation traits.
This study aims to describe the imaging features of naïve asthma patients, defined as not receiving corticosteroids or other asthma medications for at least 1 month, and their association with therapeutic response, and to discover novel unbiased imaging phenotypes. A total of 109 naïve asthma patients and 50 healthy controls were enrolled in this study. Clinical data and imaging indices of high-resolution computed tomography were collected. The correlation between imaging indices and clinical features was analyzed. Cluster analyses were adopted to determine three novel imaging phenotypes. Compared with healthy controls, naïve asthma patients presented higher scores of airway remodeling, bronchiectasis, and mucus plugs. Mean airway wall area (WA)% was inversely correlated with mid-expiratory flow velocity% predicted. The extent score of bronchiectasis was positively correlated with smoking history and significantly increased in the high mucus group. Mucus plugs were related to improving lung function and type 2 (T2) inflammation, as assessed by sputum and blood eosinophils and fraction of exhaled nitric oxide. Cluster 1 patients had a high proportion of emphysema, the best lung function, and the lowest T2 inflammation; cluster 2 patients had severe airway remodeling, relatively good lung function, and moderate T2 inflammation; cluster 3 patients had severe airway remodeling, mucus plugs, and bronchiectasis, and showed the worst lung function and highest T2 inflammation. Naïve asthma patients had the imaging traits of airway remodeling, bronchiectasis, and mucus plugs. The unbiased imaging phenotypes had good consistency with clinical characteristics, therapeutic response, and T2 inflammation expression in naïve asthma patients.


Screening asymptomatic siblings for vesicoureteral reflux: sound science or religious rhetoric?
Many urologists endorse the concept of screening asymptomatic siblings of children known to have vesicoureteral reflux. Others oppose screening until there is better evidence to justify the cost and potential morbidity of adopting a widespread screening program. A literature review of the following topics was carried out: 1) screening programs in general; 2) reflux in general; 3) familial reflux; and 4) screening for familial reflux. The evidence supporting our traditional surgical and medical management strategies for reflux is weak. The evidence supporting screening is lacking. Public Health organizations do not address the issue of screening for this condition. Despite this, there is a significant body of peer reviewed literature and compelling expert opinion, in support of screening. Possible reasons for this are explored. A randomized controlled trial to definitively assess the utility of screening would be larger and more challenging to perform than any ever done in the history of this condition. Until such time that high quality evidence exists, screening of asymptomatic siblings will continue to be based upon our individual clinical experience and teachings, the morbidity of the index case, and socioeconomic factors. We must continue to re-evaluate our management strategies for this condition in light of new information as it accrues.


Laparoscopic Liver Resection Utilizing a Water Jet Scalpel for Patients With Liver Fibrosis.
Introduction A variety of devices are utilized in order to resect liver parenchyma in laparoscopic liver resection. However, liver fibrosis makes hepatectomy problematic because the liver is rigid and prone to bleeding. The water jet scalpel, which dissociates the liver parenchyma with a jet stream has no thermal damage and is clinically utilized in liver resection, but its safety and efficacy during laparoscopic liver resection for patients with liver fibrosis remain unknown. Methods We analyzed patients who underwent laparoscopic liver resection utilizing the water jet scalpel with liver fibrosis at our hospital. A water jet scalpel was used for liver parenchymal transection, and a saline-linked ball-tipped electrocautery was simultaneously used for hemostasis. Results Subsectionectomy was one case, left lateral sectionectomy was two cases, and non-anatomical liver resection was three cases. The median blood loss was 70 mL (24-104 mL). There was no need for the intraoperative Pringle's maneuver. No perioperative blood transfusion was performed, and there were no postoperative complications, including posthepatectomy liver failure. Conclusion It was suggested that laparoscopic liver resection in patients with liver fibrosis can be safely performed with the water jet scalpel.


[Hormonal therapy in breast cancer].
Hormonal therapy has been the first systemic treatment against breast cancer. Up to now Tamoxifen and ovarian supression/ablation were the best optionts we had to treat early breast cancer as advancer disease. The advent of aromatase inhibitors, new SERMS and antistrogen Fulvestrant have supoused a great advance in the treatment of this disease and at the same time have complicated the election of the optimal drug for each patient. This article tries to review the aviable treatment options insiting on its indications.


Utility of plasma free metanephrines for detecting childhood pheochromocytoma.
Measurements of plasma free metanephrines, normetanephrine (NMN) and metanephrine (MN), provide a sensitive test for diagnosis of pheochromocytoma in adults but have not been evaluated in children. We therefore established reference ranges for plasma and urinary metanephrines and the catecholamines, norepinephrine (NE) and epinephrine (E), in 86 healthy children (age 5-17). A group of 158 healthy adults (age 18-72) served as a comparison group. Pediatric reference ranges were applied to examine the diagnostic utility of the various tests in 45 children evaluated for pheochromocytoma (age 8-17; 38 with von Hippel-Lindau syndrome), with tumors found on 12 occasions. Upper reference limits for E and MN were higher and those for NE and NMN lower in children than in adults. Boys had higher plasma levels of E and MN and higher urinary excretion of all four amines than girls. Plasma free metanephrines provided a diagnostic test with values for sensitivity (100%) and specificity (94%) that were equal to or higher than those of other tests. In two children screened for pheochromocytoma on multiple occasions, use of pediatric reference ranges for plasma free metanephrines indicated the tumor a year earlier than indicated using adult reference ranges. The findings indicate that plasma free metanephrines provide a sensitive tool for detection of pheochromocytoma in children. Age appropriate reference ranges should be used and gender differences should be considered.


Wolfram syndrome with vitelliform retinal deposits.
: Wolfram Syndrome is a rare genetic disorder usually inherited in an autosomal recessive manner. The acronym DIDMOAD characterizes the classic constellation of findings: diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. However, other ocular and systemic manifestations may also be present. The aim of this report is to present a patient with Wolfram Syndrome presenting with vitelliform changes in the retina - an association that has not been previously reported. : Case Report. : Ophthalmologic examination and imaging studies showed bilateral optic neuropathy and scattered bilateral subretinal vitelliform deposits. Genetic testing was positive for Wolfram Syndrome. : This patient showed optic atrophy with associated vitelliform retinal changes. The previously unreported association of these findings present possible associations in the molecular pathophysiology underlying both Wolfram syndrome and the spectrum of retinal disorders associated with vitelliform changes.


In vitro activity and microbiological efficacy of tedizolid (TR-700) against Gram-positive clinical isolates from a phase 2 study of oral tedizolid phosphate (TR-701) in patients with complicated skin and skin structure infections.
Tedizolid (TR-700, formerly torezolid) is the active moiety of the prodrug tedizolid phosphate (TR-701), a next-generation oxazolidinone, with high potency against Gram-positive species, including methicillin-resistant Staphylococcus aureus (MRSA). A recently completed randomized, double-blind phase 2 trial evaluated 200, 300, or 400 mg of oral tedizolid phosphate once daily for 5 to 7 days in patients with complicated skin and skin structure infections. This report examines the in vitro activity of tedizolid and Zyvox (linezolid) against Gram-positive pathogens isolated at baseline and describes the microbiological and clinical efficacy of tedizolid. Of 196 isolates tested, 81.6% were S. aureus, and of these, 76% were MRSA. The MIC(50) and MIC(90) of tedizolid against both methicillin-susceptible S. aureus (MSSA) and MRSA were 0.25 μg/ml, compared with a MIC(50) of 1 μg/ml and MIC(90) of 2 μg/ml for linezolid. For coagulase-negative staphylococci (n = 7), viridans group streptococci (n = 15), and beta-hemolytic streptococci (n = 3), the MICs ranged from 0.03 to 0.25 μg/ml for tedizolid and from 0.12 to 1 μg/ml for linezolid. The microbiological eradication rates at the test-of-cure visit (7 to 14 days posttreatment) in the microbiologically evaluable population (n = 133) were similar in all treatment groups, with overall eradication rates of 97.7% for all pathogens, 97.9% for MRSA, and 95.7% for MSSA. The clinical cure rates for MRSA and MSSA infections were 96.9% and 95.7%, respectively, across all dose groups. This study confirms the potent in vitro activity of tedizolid against pathogenic Gram-positive cocci, including MRSA, and its 4-fold-greater potency in comparison with linezolid. All dosages of tedizolid phosphate showed excellent microbiological and clinical efficacy against MRSA and MSSA.


A physicist looks at bacterial chemotaxis.
What is distinctive about bacterial chemotaxis, as compared to, for example, taste in the elephant, is the time over which decisions must be made. The lower limit is set by diffusion of chemicals to and from the cell surface, which demands long times for statistically significant counts. The upper limit is set by diffusion of the cell itself, which demands short times for well-defined swimming paths. For an organism the size of E. coli, temporal comparisons of the concentrations of chemicals in the environment must be made within a few seconds. Although such short time spans might be difficult for the biochemist, they are not so difficult for E. coli, because diffusion can carry a small molecule across the cell in about 1 msec. E. coli has the opposite problem: How does it integrate inputs from many receptors over periods 1000 times as long? The mechanisms for this signal processing are beginning to be understood. We know how most chemical attractants are identified, how temporal comparisons might be made, and how the behavioral output is effected. We know less about how sensory information crosses the cytoplasmic membrane, how the reactions that link the receptors to the flagella generate such high gain, and what actually controls the direction of flagellar rotation. One thing is quite clear: E. coli demands our admiration and respect.


Studies with 1,2-dithiole-3-thione as a chemoprotector of hydroquinone-induced toxicity to DBA/2-derived bone marrow stromal cells.
Stromal cells from DBA/2 mouse bone marrow have been shown to be susceptible to cytotoxicity induced by several redox-active metabolites of benzene, including hydroquinone (HQ). Treatment with HQ also alters the composition of stromal cell populations by preferentially killing stromal macrophages compared to stromal fibroblasts. This cytotoxicity can be prevented by 1,2-dithiole-3-thione (DTT) as a result of the induction of quinone reductase (QR), a quinone-processing enzyme, and glutathione. The inductive activities of DTT protected stromal cells against HQ-induced cytotoxicity and against HQ-induced impairment of stromal cell ability to support myelopoiesis. In vivo feeding of DTT to DBA/2 mice increased QR activity within the bone marrow compartment and protected bone marrow stromal cells isolated from the DTT-fed animals from ex vivo HQ challenge. Thus, the inducibility of cellular defense mechanisms and xenobiotic-processing enzymes by chemoprotective agents such as DTT may be a useful strategy for protecting against chemically induced bone marrow toxicities.


[Distribution of Xin'an TCM physicians and their medical works and the reasons of its formation of medical center].
Based on the living times, native places and medical works of Xin'an TCM physicians described in the Xin an ming yi kao(Textual Research of Famous Physicians of Xin'an Region), the geographical distribution of ancient TCM physicians was analyzed by using Excel software. It is found that Xin'an medicine was originated from the Eastern Jin Dynasty and highly developed in the Qing Dynasty, and the number of its TCM physicians in the Ming and Qing Dynasties was large than the summation of those from the Eastern Jin Dynasty to the Ming Dynasty. In regard to the district, the distribution of Xin'an TCM physicians was characterized by more in the southeastern and less in the northwestern parts, forming a distribution area concentrated in the three counties of Shexian, Wuyuan and Xiuning. The reasons of such concentration of Xin'an TCM physicians are closely related to the economic growth, the influence of Neo-Confucianism and the density of population.


Mechanisms of initiation and progression of intestinal fibrosis in IBD.
Intestinal fibrosis is a common complication of the inflammatory bowel diseases (IBDs). It becomes clinically apparent in >30% of patients with Crohn's disease (CD) and in about 5% with ulcerative colitis (UC). Fibrosis is a consequence of local chronic inflammation and is characterized by excessive extracellular matrix (ECM) protein deposition. ECM is produced by activated myofibroblasts, which are modulated by both, profibrotic and antifibrotic factors. Fibrosis depends on the balance between the production and degradation of ECM proteins. This equilibrium can be impacted by a complex and dynamic interaction between profibrotic and antifibrotic mediators. Despite the major therapeutic advances in the treatment of active inflammation in IBD over the past two decades, the incidence of intestinal strictures in CD has not significantly changed as the current anti-inflammatory therapies neither prevent nor reverse the established fibrosis and strictures. This implies that control of intestinal inflammation does not necessarily affect the associated fibrotic process. The conventional view that intestinal fibrosis is an inevitable and irreversible process in patients with IBD is also gradually changing in light of an improved understanding of the cellular and molecular mechanisms that underline the pathogenesis of fibrosis. Comprehension of the mechanisms of intestinal fibrosis is thus vital and may pave the way for the developments of antifibrotic agents and new therapeutic approaches in IBD.


Horizontal cell morphology in nocturnal and diurnal primates: a comparison between owl-monkey (Aotus) and capuchin monkey (Cebus).
Horizontal cell morphology was studied in the retina of the nocturnal owl-monkey, Aotus, and compared with that of its diurnal, close relative, the capuchin monkey, Cebus . Cells were initially labeled with DiI and the staining was later photoconverted in a stable precipitated using DAB as chromogen. The sizes of cell bodies, dendritic fields, and axon terminals, number of dendritic clusters, intercluster spacing, and intercone spacing were measured at increasing eccentricities. Two distinct morphological classes of horizontal cells were identified, which resembled those of H1 and H3 cells described in diurnal monkeys. A few examples of a third class, possibly corresponding to the H2 cells of diurnal monkeys, were labeled. Both H1 and H3 cells increased in size and had increasing numbers of dendritic clusters with eccentricity. H3 cells were larger and had a larger number of dendritic clusters than H1 cells. Owl-monkey H1 cells had larger dendritic fields than capuchin monkey H1 cells at all quadrants in the central and midperipheral retinal regions, but the difference disappeared in the far periphery. Owl-monkey and capuchin monkey H1 cells had about the same number of dendritic clusters across eccentricity. As owl-monkey H1 cells were larger than capuchin monkey H1 cells, the equal number of clusters in these two primates was due to the fact that they were more spaced in the owl-monkey cells. H1 intercluster distance closely matched intercone spacing for both the owl-monkey and capuchin monkey retinas. On the other hand, H3 intercluster distance was larger than intercone spacing in the retina of both primates. Owl-monkey H1 axon terminals had 2-3 times more knobs than capuchin monkey H1 axon terminals in spite of having about the same size and, consequently, knob density was 2-3 times higher for owl-monkey than capuchin monkey H1 axon terminals across all eccentricities. The differences observed between owl-monkey and capuchin monkey horizontal cells, regarding the morphology of their dendritic trees and axon terminals, may be related to the differences found in the cone-to-rod ratio in the retina of these two primates. They seem to represent retinal specializations to the nocturnal and diurnal life styles of the owl-monkey and capuchin monkey, respectively.


N-terminal ProBNP levels can predict cardiac failure after cardiac surgery.
The aim of this study was to evaluate the relationship between the preoperative N-terminal pro-B-type natriuretic peptide (NT-proBNP) level and the need for the inotropic support in the early postoperative period of patients undergoing coronary artery bypass graft surgery. The patients were divided into 2 groups: NT-proBNP level<220 pg/ml (group A, n=26) or >220 pg/ml (group B, n=26). The normal value for NT-proBNP level was accepted as <220 pg/ml. The cardiac output was measured on arrival in intensive care and at the 16th hour. The groups were compared with respect to early postoperative hemodynamic measurements, urinary output, use of inotropic agents and requirement for additional cardiac-assist devices. Left ventricular ejection fraction, cardiac output and cardiac index were lower in group B and inotropic agents were used for a longer period of time and at higher doses in this group (p<0.05). Measurement of the NT-proBNP level in the period before cardiac surgery can indicate the postoperative prognosis of the patient and may be a predictor of the need for postoperative inotropic treatment.


Fracture heuristics: surgical decision for approaches to distal radius fractures. A surgeon's perspective.
Introduction: The aim of the present study is to develop a heuristic that could replace the surgeon's analysis for the decision on the operative approach of distal radius fractures based on simple fracture characteristics. Patients and methods: Five hundred distal radius fractures operated between 2011 and 2014 were analyzed for the surgeon's decision on the approach used. The 500 distal radius fractures were treated with open reduction and internal fixation through palmar, dorsal, and dorsopalmar approaches with 2.4 mm locking plates or underwent percutaneous fixation. The parameters that should replace the surgeon's analysis were the fractured palmar cortex, and the frontal and the sagittal split of the articular surface of the distal radius. Results: The palmar approach was used for 422 (84.4%) fractures, the dorsal approach for 39 (7.8%), and the combined dorsopalmar approach for 30 (6.0%). Nine (1.8%) fractures were treated percutaneously. The correlation between the fractured palmar cortex and the used palmar approach was moderate (r=0.464; p<0.0001). The correlation between the frontal split and the dorsal approach, including the dorsopalmar approach, was strong (r=0.715; p<0.0001). The sagittal split had only a weak correlation for the dorsal and dorsopalmar approach (r=0.300; p<0.0001). Discussion: The study shows that the surgical decision on the preferred approach is dictated through two simple factors, even in the case of complex fractures. Conclusion: When the palmar cortex is displaced in distal radius fractures, a palmar approach should be used. When there is a displaced frontal split of the articular surface, a dorsal approach should be used. When both are present, a dorsopalmar approach should be used. These two simple parameters could replace the surgeon's analysis for the surgical approach.


Formulation of diltiazem affects cyclosporin-sparing activity.
To consider the effect of changing from a conventional release formulation of diltiazem to the controlled diffusion diltiazem formulation on the cyclosporin-sparing effect in kidney transplant recipients. Seven stable renal transplant recipients were studied on two separate occasions following at least 2 weeks stabilisation on either formulation. The order of administration of the two formulations was not randomised as all patients were already prescribed lower dosages of diltiazem before entering this phase of a larger study. The doses of diltiazem used were 90 mg (conventional release diltiazem) taken twice daily and 180 mg controlled diffusion diltiazem taken in the morning. Whilst there were no overall significant differences between the two formulations, the study demonstrated considerable interpatient variability when changing to the controlled diffusion formulation, particularly following the morning cyclosporin dose, with three patients showing a reduced cyclosporin AUC (30-60%) and one an increased cyclosporin AUC of 36%. A change in formulation of the cyclosporin-sparing agent may result in unpredictable alterations in cyclosporin concentrations and resultant clinical sequelae.


Real-Time Imaging of Endocytosis and Intracellular Trafficking of Semiconducting Polymer Dots.
Semiconducting polymer dots (Pdots) have shown great promise in biomedical applications, including biosensing, drug delivery, and live imaging of cells and biomolecules. Insight into the mechanism and regulation of cellular uptake and intracellular metabolism of Pdots is important for the development of superior Pdots-based theranostic nanoconjugates. Herein, we performed real-time imaging of endocytosis and intracellular trafficking of a type of fluorescent Pdots that showed excellent biocompatibility in various types of cells. The endocytic routes and kinetics of Pdots were differently regulated in distinct cell types. Following endocytosis, Pdots were transported in vesicles along microtubule and destined for lysosomes. Furthermore, our results revealed exosome-mediated extracellular release of Pdots and have tracked the dynamic process at the single particle level. These results provide new insight into the design of more effective and selective imaging probes as well as drug carriers.


From Ligand to Phosphor: Rapid, Machine-Assisted Synthesis of Substituted Iridium(III) Pyrazolate Complexes with Tuneable Luminescence.
A first-generation machine-assisted approach towards the preparation of hybrid ligand/metal materials has been developed. A comparison of synthetic approaches demonstrates that incorporation of both flow chemistry and microwave heating can be successfully applied to the rapid synthesis of a range of new phenyl-1H-pyrazoles (ppz) substituted with electron-withdrawing groups (-F, -CF3 , -OCF3 , and -SF5 ). These, in turn, can be translated into heteroleptic complexes, [Ir(ppz)2 (bipy)]BF4 (bipy=2,2'-bipyridine). Microwave-assisted synthesis for the IrIII complexes allows isolation of spectroscopically pure species in less than 1 h of reaction time starting from IrCl3 . All of the new complexes have been characterised photophysically (including nanosecond time-resolved transient absorption spectroscopy), electrochemically, and by TD-DFT studies. The complexes exhibit ligand-dependent, tuneable, green-yellow luminescence (500-560 nm), with quantum yields in the range 5-15 %.


[Anesthetic Management for Laparoscopic Surgery in a Very Elderly Patient with Severe Mitral Regurgitation].
A 90-year-old woman with severe mitral regurgitation underwent laparoscopic cholecystectomy. In her anesthetic management, we used FloTrac system and monitored arterial pressure-based cardiac index (CI), stroke volume (SV), and stroke volume variation (SVV) continuously as the indicators of intraoperative hemodynamics. Although the blood pressure fluctuated highly in Fowler position especially, we could control hemodynamics appropriately by intermittent volume infusion and adjusting administration of cardiovascular agents under monitoring these indicators. In a very elderly patient with severe mitral regurgitation, anesthesia and operation may cause severe circulatory disturbances. Therefore, it is important to select proper monitoring as stated above and maintain hemodynamics with the utmost care and attention.


Polypyrrole actuator with a bioadhesive surface for accumulating bacteria from physiological media.
A gold/polypyrrole (Au/PPy) bilayer actuator was fabricated by electrochemical deposition, and its surface was modified with a bioadhesive polymer, polydopamine. The actuator exhibited high performances of actuation in physiological media. Furthermore, the surface of the actuator is sticky in water and thus can seize bacteria from their aqueous solutions. Actuation greatly increased the efficiency of adhering bacteria on the actuator surface, and this technique provides a cheap and convenient approach for accumulating bacteria from physiological media.


Experimental creation of a fully inseparable tripartite continuous-variable state.
A continuous-variable tripartite entangled state is experimentally generated by combining three independent squeezed vacuum states, and the variances of its relative positions and total momentum are measured. We show that the measured values violate the separability criteria based on the sum of these quantities and prove the full inseparability of the generated state.


Identification of a promoter motif involved in Curtovirus sense-gene expression in transgenic Arabidopsis.
Expression of the seven open reading frames (ORFs) of single-stranded DNA Curtoviruses such as Beet curly top virus (BCTV) and Beet severe curly top virus (BSCTV) is driven by a bi-directional promoter. To investigate this bi-directional promoter activity with respect to viral late gene expression, transgenic Arabidopsis plants expressing a GUS reporter gene under the control of either the BCTV or BSCTV bi-directional promoter were constructed. Transgenic plants harboring constructs showed higher expression levels when the promoter of the less virulent BCTV was used than when the promoter of the more virulent BSCTV was used. In transgenic seedlings, the reporter gene constructs were expressed primarily in actively dividing tissues such as root tips and apical meristems. As the transgenic plants matured, reporter gene expression diminished but viral infection of mature transgenic plants restored reporter gene expression, particularly in transgenic plants containing BCTV virion-sense gene promoter constructs. A 30 base pair conserved late element (CLE) motif was identified that was present three times in tandem in the BCTV promoter and once in that of BSCTV. Progressive deletion of these repeats from the BCTV promoter resulted in decreased reporter gene expression, but BSCTV promoters in which one or two extra copies of this motif were inserted did not exhibit increased late gene promoter activity. These results demonstrate that Curtovirus late gene expression by virion-sense promoters depends on the developmental stage of the host plant as well as on the number of CLE motifs present in the promoter.


Mast cell distribution in nodules of Onchocerca volvulus from untreated patients with generalized onchocerciasis.
Onchocercomata with a defined worm population were analysed to elucidate the distribution of mast cells. Nodules with live females were classified according to the presence or absence of microfilariae. Immunohistochemical staining was performed using antibodies specific for mast cells or IgE. Mast cells appeared singly or in diffuse accumulations perivascularly and in inflammatory infiltrates between adult Onchocerca volvulus and in the capsular area. No mast cells were detected in cystic parts. Only few, scattered mast cells were found in the fibrous zone around the adult worm. They were increased with stronger infiltration and hence, related to the inflammatory cells. Mast cells were never localized directly at adult worms or microfilariae. A correlation of the mast cell distribution to the occurrence of eosinophils was observed regarding higher numbers of mast cells and eosinophils in nodules with microfilariae-producing females. Nodules with single males revealed higher numbers of mast cells than nodules with non-producing females, although both contained very few eosinophils. Onchocercomata with dead worms contained significantly more mast cells than those with live filariae. In conclusion, the localization and frequency of mast cells is contingent on the vitality and productivity of the worms and therefore, indirectly and directly on the release of O. volvulus antigens.


The prognostic significance of hypertension at diagnosis in children with wilms tumor.
To determine the prognostic effect of hypertension at diagnosis on outcomes of children with Wilms tumor (WT). Methods: A single center retrospective analysis was conducted on 85 consecutive children with WT diagnosed between January 2000 and August 2013. Patients were classified as hypertensive or normotensive at diagnosis. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Cox regression was used to determine the predictive significance of hypertension and other clinical factors. Results: Seventy-one patients had complete data. Of this, 25 (35.2%) were hypertensive and 46 (64.8%) normotensive with corresponding remission rates of 56.0% versus 82.6%, p=0.032; and death as first event of 7% versus 0%, p=0.004. The 5-year OS in the hypertensive versus normotensive patients were (67.1±10.3% versus 89.6±4.9%, p=0.009) and the corresponding 5-year PFS were (53.4±10.4% versus 79.1±6.2%, p=0.007). With univariate analysis, hypertension and local stage were predictors of OS (p=0.012 and p=0.029) and PFS (p=0.030 and p=0.008). In the multivariate analysis, hypertension, local stage, and histopathology were identified as independent prognostic factors of OS (p=0.004, p=0.034, and p=0.038); and hypertension and local stage as prognostic for PFS (p=0.010 and p=0.012). Conclusion: Hypertension at diagnosis is a prognostic predictor of poor outcome in WT and may signify tumor resistance.


[Epilepsy in chromosome aberrations].
Epilepsy is among the most frequent finding in many chromosome aberrations. While most chromosome aberrations can be associated with different seizure types, there are few aberrations which feature specific seizures and EEG patterns. Among the 400 different chromosomal imbalances described with seizures and EEG abnormalities, eight have a high association with epilepsy. These comprise: the monosomy 1p36, Wolf-Hirschhorn syndrome (4p-), Angelman syndrome, Miller-Dieker del 17p13.3, the inversion duplication 15 syndrome, ring 20 and ring 14 syndromes, Down's syndrome. These chromosomal regions where aberrations have an evident association with epilepsy may be useful targets for gene hunters. On the other hand, a better characterisation of epileptic syndrome in these disorders may lead to a better and specific treatment.


[A Single-Stage Combined Supra- and Infra-Sellar Approach for Recurrent Large Pituitary Adenomas:Report of Two Cases].
Despite the recent technological advances in operative instruments and development of novel techniques for endoscopic skull-base surgeries, surgical treatment of primary or recurrent large/giant pituitary adenomas remains a challenge. Postoperative hemorrhage from the residual tumor and the associated impairment of the adjacent cranial nerve functions can cause severe morbidity. To manage such operative risks, a combined supra- and infra-sellar approach(CSISA)can be used as a surgical option for difficult-to-resect large/giant pituitary adenomas. We successfully performed a single-stage CSISA in two patients with large recurrent pituitary adenomas with favorable outcomes. Both patients had recurrent adenomas after multiple trans-sphenoidal surgeries and presented with visual impairment due to tumor regrowth. Each tumor had a maximum diameter of more than 4 cm. One tumor extended into the anterior skull base, while the other extended into the supra-sellar region with extremely lateral invasion. The CSISA helped surgeons visualize the tumors and the surrounding structures through a combination of different operative views. Subtotal resection was safely achieved in both cases, with no postoperative hemorrhage and deterioration of visual and pituitary function. The CSISA is useful not only for pituitary adenomas with anterior or lateral extension and multi-lobular growth, but also for certain cases with recurrent large/giant pituitary adenomas.


The Effects of Background and Interference Selection on Patterns of Genetic Variation in Subdivided Populations.
It is well known that most new mutations that affect fitness exert deleterious effects and that natural populations are often composed of subpopulations (demes) connected by gene flow. To gain a better understanding of the joint effects of purifying selection and population structure, we focus on a scenario where an ancestral population splits into multiple demes and study neutral diversity patterns in regions linked to selected sites. In the background selection regime of strong selection, we first derive analytic equations for pairwise coalescent times and FST as a function of time after the ancestral population splits into two demes and then construct a flexible coalescent simulator that can generate samples under complex models such as those involving multiple demes or nonconservative migration. We have carried out extensive forward simulations to show that the new methods can accurately predict diversity patterns both in the nonequilibrium phase following the split of the ancestral population and in the equilibrium between mutation, migration, drift, and selection. In the interference selection regime of many tightly linked selected sites, forward simulations provide evidence that neutral diversity patterns obtained from both the nonequilibrium and equilibrium phases may be virtually indistinguishable for models that have identical variance in fitness, but are nonetheless different with respect to the number of selected sites and the strength of purifying selection. This equivalence in neutral diversity patterns suggests that data collected from subdivided populations may have limited power for differentiating among the selective pressures to which closely linked selected sites are subject.


A Simple Technique to Manage Anxiety During Tooth Extraction.
Pain-free dental treatment is important for reducing anxiety, treatment completion, and enhancing acceptance of future dental treatment. Injectable local anesthesia assists this pain-free approach but can cause anxiety in few patients. Achieving proper anesthesia is important to complete the procedure successfully, thereby adding to patient's care and comfort. This article describes a simple technique to manage dental anxiety using virtual reality headset. Audio visual aid helped the patient to relax and eliminate the phobia of local anesthesia injection during surgical tooth extraction. The simple technique enhanced the patient's ability to continue the dental procedure.


Domains formed within the N-terminal region of the quorum-sensing activator TraR are required for transcriptional activation and direct interaction with RpoA from agrobacterium.
TraR, a quorum-sensing activator, induces transcription from its binding site, the tra-box, located upstream of Ti plasmid target promoters. TraR activated expression of a lacZ reporter in Escherichia coli only when RpoAAt from Agrobacterium tumefaciens was co-expressed. As assessed by gel retardation assays RpoAAt, but not RpoAEc, formed a ternary complex with TraR and a tra-box probe in vitro. TraR formed similar ternary complexes with alphaCTDAt but not with NTDAt, the C- and N-terminal segments of RpoAAt. As measured by surface plasmon resonance refractometry, TraR interacted directly with RpoAAt with an affinity about five times greater than that observed for its interaction with RpoAEc. The activator interacted with alphaCTDAt with kinetics and affinities similar to those of the full-sized -subunit. Positive control (PC) mutations at Asp-10 and Gly-123 of TraR did not affect DNA binding but greatly decreased the TraR-RpoAAt interaction. These two residues combine to form two patches on the activator, one of which may be involved in interaction with RpoA. When co-expressed, mutants of TraR with substitutions at Asp-10 complementing mutants with substitutions at Gly-123 for gene activation in an allele-specific manner. Co-expression studies with TraR and its PC mutants, and also with complementary PC alleles of TraR, coupled with three-dimensional structure are consistent with a hypothesis that both Asp-10/Gly-123 patches are required for activator function.


Right ventricular involvement and pulmonary hypertension in an elderly woman with tako-tsubo cardiomyopathy.
We describe a case of tako-tsubo cardiomyopathy in an elderly woman with a permanent pacemaker admitted to the ED with chest pain and dyspnea. Coronary angiography revealed normal coronary arteries. Typical left ventricular apical ballooning was demonstrated on contrast ventriculography. Left and right ventricular ballooning with pulmonary artery systolic hypertension was detected by transthoracic echocardiography. Velocity vector imaging and strain analysis showed a typical pattern of regional myocardial apical right ventricular contraction characterized by paradoxical positive longitudinal systolic strain. Biventricular involvement was associated with hemodynamic instability, signs of pulmonary vascular congestion, and bilateral basal pleural effusion. The patient's clinical condition gradually improved, and she was discharged after prolonged hospitalization. Predischarge echocardiography showed substantial recovery of left and right systolic function along with normalization of pulmonary artery systolic pressure. Right ventricular function should be carefully evaluated in patients with tako-tsubo cardiomyopathy, especially in the acute phase.


Phenotypic characterization of macrophages in human term placenta.
Immunohistological techniques have been used to study heterogeneity, frequency and distribution of macrophages and T lymphocytes in chorionic villous mesenchyme, stroma of the amniochorion and decidua of 36 human term placentas obtained at spontaneous normal delivery and by caesarean section, using a panel of monoclonal antibodies (mAb) specific for macrophage phenotypes appearing in acute early (mAb 27E10), late (mAb 25F9) and down-regulatory (mAb RM3/1) stages of inflammation. Significant numbers of macrophages were identified. It could be shown that RM3/1+ macrophage phenotypes which in vitro are strongly dexamethasone-inducible and in vivo appear in down-regulatory stages of inflammatory processes are the major cell population in human term placenta. Macrophages characterized by monoclonal antibodies 27E10 and 25F9, as well as CD4+ and CD8+ cells, were distributed sparsely or were completely absent. The finding of anti-inflammatory macrophage phenotypes to be the predominant mononuclear cell population in human term placenta provides support for a mechanism whereby placenta functions as an active immunosuppressive biological barrier between mother and fetus.


Match-Play Demands of Elite U17 Hurlers During Competitive Matches.
Young, D, Mourot, L, Beato, M, and Coratella, G. Match-play demands of elite U17 hurlers during competitive matches. J Strength Cond Res 34(7): 1982-1989, 2020-The current study aimed to quantify the match-play workload in elite male under 17 hurlers, measuring the differences between the first and second halves and between positions. Global positioning system (10-Hz) and heart rate monitors were used to collect data from 76 players during 18 matches. Players' total distance (TD), relative distance (RD), high-speed running (HSR), the number and length of sprints, and the total sprint distance (TSD) was 6,483 ± 1,145 m, 108 ± 19 m·min, 583 ± 215 m, 18 ± 6, 15 ± 3 m, and 272 ± 77 m, respectively. Peak and mean heart rate were 194 ± 8 b·min and 167 ± 4 b·min, respectively. Decrements in TD (p < 0.001, effect size [ES] = 0.72), RD (p < 0.001, ES = 0.72), HSR (p < 0.001, ES = 0.55), the number of sprints (p < 0.001, ES = 0.57), mean length of sprint (p < 0.011, ES = 0.25), TSD (p < 0.001, ES = 0.69), mean heart rate (p < 0.001, ES = 0.35), and peak heart rate (p < 0.001, ES = 0.52) were found between halves. Largely-to-very largely greater TD, RD, and HSR were covered by midfielders, half-backs, and half-forwards compared with full-backs and full-forwards. No between-position difference was found in peak and mean heart rate. The current results are the first to highlight the differences in external and internal position-specific workload in elite male under 17 hurlers. Coaches need to consider the position-specific demands and between-half drop-off to prepare young hurlers appropriately to repeat the match-play performances of competition.


Powerful and Real-Time Quantification of Antifungal Efficacy against Triazole-Resistant and -Susceptible Aspergillus fumigatus Infections in Galleria mellonella by Longitudinal Bioluminescence Imaging.
Aspergillus fumigatus is an environmental mold that causes life-threatening respiratory infections in immunocompromised patients. The plateaued effectiveness of antifungal therapy and the increasing prevalence of triazole-resistant isolates have led to an urgent need to optimize and expand the current treatment options. For the transition of in vitro research to in vivo models in the time- and resource-consuming preclinical drug development pipeline, Galleria mellonella larvae have been introduced as a valuable in vivo screening intermediate. Despite the high potential of this model, the current readouts of fungal infections in G. mellonella are insensitive, irreproducible, or invasive. To optimize this model, we aimed for the longitudinal quantification of the A. fumigatus burden in G. mellonella using noninvasive bioluminescence imaging (BLI). Larvae were infected with A. fumigatus strains expressing a red-shifted firefly luciferase, and the substrate dosage was optimized for the longitudinal visualization of the fungal burden without affecting larval health. The resulting photon flux was successfully validated for fungal quantification against colony forming units (CFU) analyses, which revealed an increased dynamic range from BLI detection. Comparison of BLI to survival rates and health index scores additionally revealed improved sensitivity for the early discrimination of differences in fungal burdens as early as 1 day after infection. This was confirmed by the improved detection of treatment efficacy against triazole-susceptible and -resistant strains. In conclusion, we established a refined G. mellonella aspergillosis model that enables the noninvasive real-time quantification of A. fumigatus by BLI. This model provides a quick and reproducible in vivo system for the evaluation of treatment options and is in line with 3Rs recommendations. IMPORTANCE Triazole-resistant Aspergillus fumigatus strains are rapidly emerging, and resistant infections are difficult to treat, causing mortality rates of up to 88%. The recent WHO priority list underscores A. fumigatus as one of the most critical fungal pathogens for which innovative antifungal treatment should be (urgently) prioritized. Here, we deliver a Galleria mellonella model for triazole-susceptible and -resistant A. fumigatus infections combined with a statistically powerful quantitative, longitudinal readout of the A. fumigatus burden for optimized preclinical antifungal screening. G. mellonella larvae are a convenient invertebrate model for in vivo antifungal screenings, but so far, the model has been limited by variable and insensitive observational readouts. We show that bioluminescence imaging-based fungal burden quantification outperforms these readouts in reliability, sensitivity, and time to the detection of treatment effects in both triazole-susceptible and -resistant infections and can thus lead to better translatability from in vitro antifungal screening results to in vivo confirmation in mouse and human studies.


Microsurgical aesthetic treatment of gingival fenestration by a coronally repositioned partial thickness graft: a case report.
Gingival fenestration is a rare pathological entity, scarcely described in the literature. The present paper has reported a case of a 22-year-old male patient with a "Gingival fenestration" in the lower left central incisor. The lesion was successfully treated using a coronally positioned partial thickness graft under 4 X magnification, with excellent aesthetic results.


Successful Use of Recombinant Activated Factor VII to Reverse Ticagrelor-Induced Bleeding Risk: A Case Report.
Management of ticagrelor-associated bleeding is challenging, especially in neurosurgery. Platelet transfusion is inefficient and no antidote is currently available. We report here the first case of recombinant activated factor VII (rFVIIa) use to bypass ticagrelor-induced platelet inhibition. A woman treated with ticagrelor and requiring emergent neurosurgery for an intracranial hematoma received preoperative high-dose platelet transfusion and 60 μg/kg rFVIIa. Laboratory monitoring demonstrated that platelet transfusion failed to reverse ticagrelor-induced platelet inhibition while rFVIIa improved hemostasis by shortening the thromboelastometric clotting time. Neurosurgery occurred without any bleeding event but the patient presented with a postoperative pulmonary embolism. In conclusion, rFVIIa may decrease ticagrelor-induced bleeding risk but careful assessment of the benefit-risk balance is warranted before using rFVIIa to reverse ticagrelor effects.


The role of intracellular acidification in antigen processing.
The experiments described here were designed to investigate the role of intracellular acidic organelles in the processing of foreign antigens. Simultaneous addition of antigen and the inactive precursor of an acid protease, cathepsin L, greatly diminished the stimulation of a T-cell hybridoma specific for pigeon cytochrome c. The effect occurred during antigen processing as the presentation of a peptide fragment was unaffected by precursor-cathepsin L. The effect required uptake of the enzyme via mannose-6-PO4 receptors and was specific for antigenic determinants cleavable by the enzyme. The results confirm, without any pharmacologic manipulation, that foreign antigen moves into an acidic environment during some phase of its processing. We also explored the role in antigen processing of one acidic compartment, the early endosome, by examining CHO cells expressing a temperature-sensitive defect in endosomal acidification. These cells were transfected with MHC class II genes to convert them into APC for CD4+T cells. When these cells were incubated at the nonpermissive temperature, their ability to process antigen was impaired. There was no negative effect on presentation of antigenic peptides nor on the uptake and degradation of the antigen. Wildtype CHO cells similarly transfected and tested did not show any aberrancy in antigen processing. The inhibition of processing by the mutant cells was only partial, even under stringent conditions, and the residual processing was eliminated by chloroquine. Our findings provide the first evidence for a contribution by acidified early endosomes to the pathway of antigen processing and suggest that other acidified compartments are also involved.


Multiple Level Effects of Imazethapyr on Leptodactylus latinasus (Anura) Adult Frogs.
Imazethapyr is an herbicide that is used in a variety of crops worldwide, including soybean and corn. The aim of the present study was to evaluate the biomarkers responses of adult Leptodactylus latinasus exposed to the formulation Pivot® H (10.59% imazethapyr) in the laboratory at concentrations and under conditions that simulate two potential field exposure scenarios: an immersion in field runoff (Scenario 1: 10 mg/L) and a direct exposure to the droplets emitted by spray noozles (Scenario 2: 1000 mg/L). In both scenarios, the experimental procedure involved completely immersing the frogs over a period of 15 s. Different endpoints were evaluated at several ecotoxicological levels 48 and 96 h after the herbicide exposure. These included individual (biometric indices and behavior alterations), histological (liver pigments and lesions), biochemical (catalase, glutathione system and cholinesterase activities) and genotoxic effects (micronuclei induction and nuclear abnormalities). Forty-eight hours after imazethapyr exposure, frogs submitted to Scenario 1 presented an inhibition of liver glutathione-S-transferase activity, whereas histological alterations and increased hepatic cholinesterase levels were observed in frogs exposed under Scenario 2. Ninety-six hours after exposure to the imazethapyr formulation, frogs from the Scenario 1 treatment presented a decrease in liver melanin and hemosiderin, increased hepatic catalase activity and micronuclei induction. For their part, frogs exposed to Scenario 2 presented a decrease in the hepatosomatic index, an increase in liver alterations, melanin reduction and micronuclei induction. The multivariate analysis enables correlations to be made between biomarkers of different organizational level in exposed anurans. Our result indicates that real exposure to imazethapyr formulations under field conditions may pose a risk to Leptodactylus latinasus populations living in the agroecosystems.


Sowing the seeds of stereotypes: Spontaneous inferences about groups.
Although dispositional inferences may be consciously drawn from the trait implications of observed behavior, abundant research has shown that people also spontaneously infer trait dispositions simply in the process of comprehending behavior. These spontaneous trait inferences (STIs) can occur without intention or awareness. All research on STIs has studied STIs based on behaviors of individual persons. Yet important aspects of social life occur in groups, and people regularly perceive groups engaging in coordinated action. We propose that perceivers make spontaneous trait inferences about groups (STIGs), parallel to the STIs formed about individuals. In 5 experiments we showed that (a) perceivers made STIGs comparable with STIs about individuals (based on the same behaviors), (b) a cognitive load manipulation did not affect the occurrence of STIGs, (c) STIGs occurred for groups varying in entitativity, (d) STIGs influenced perceivers' impression ratings of those groups, and (e) STIG-based group impressions generalized to new group members. These experiments provide the first evidence for STIGs, a process that may contribute to the formation of spontaneous group impressions. Implications for stereotype formation are discussed.


Spinal Intradural Intramedullary Mature Cystic Teratoma in a Young Adult: A Rare Tumor.
Intradural mature teratomas are spinal tumors containing all the germinal layers and rarely present in adulthood. This study describes an unusual case of intradural mature teratoma in a 19-year-old male who presented with persistent lower limb pain and difficulty in micturition. The magnetic resonance imaging (MRI) scan showed heterogeneously enhancing intramedullary mass in the L3-L4 vertebral region and was associated with tethering of the spinal cord. Scalloping of the posterior aspect of vertebral body and narrowing of the pedicles were present. Subtotal excision of the tumor was done because of its adherence to the conus. Attempt to completely excise such adherent intramedullary tumors can lead to permanent neurological deficits. The tissue was sent for histopathological examination which showed tissue from all the three germinal layers confirming the diagnosis. The patient showed improvement of symptoms following the surgery. This study also compared the literature of similar cases and the treatments available for this disease.


Modelling and Optimization of Four-Segment Shielding Coils of Current Transformers.
Applying shielding coils is a practical way to protect current transformers (CTs) for large-capacity generators from the intensive magnetic interference produced by adjacent bus-bars. The aim of this study is to build a simple analytical model for the shielding coils, from which the optimization of the shielding coils can be calculated effectively. Based on an existing stray flux model, a new analytical model for the leakage flux of partial coils is presented, and finite element method-based simulations are carried out to develop empirical equations for the core-pickup factors of the models. Using the flux models, a model of the common four-segment shielding coils is derived. Furthermore, a theoretical analysis is carried out on the optimal performance of the four-segment shielding coils in a typical six-bus-bars scenario. It turns out that the "all parallel" shielding coils with a 45° starting position have the best shielding performance, whereas the "separated loop" shielding coils with a 0° starting position feature the lowest heating value. Physical experiments were performed, which verified all the models and the conclusions proposed in the paper. In addition, for shielding coils with other than the four-segment configuration, the analysis process will generally be the same.


Overlap stimulation of primary and secondary B cells by cross-reacting determinants.
Experiments were carried out to test the validity of the hypothesis that postulated differences in the nature of the antigen receptors of primary and secondary B cells should be reflected in a greater specificity in primary B-cell stimulation (2). Enumeration of clonal precursors stimulated by either DNP-Hy, TNP-Hy, or a mixture of both antigens confirmed this hypothesis. Since the sum of primary B cells stimulated by DNP-Hy and TNP-Hy is approximately equal to the number stimulated by a mixture of both, overlap stimulation of primary B cells by these antigens could be considered negligible. In contrast, the stimulation of B cells from mice previously immunized with DNP-Hy showed extensive overlap of stimulation by DNP-Hy and TNP-Hy. Thus secondary B cells appear less fastidious in their affinity requirements for stimulation than primary B cells.


Physiological significance of the plant circadian clock in natural field conditions.
For many decades, researchers have focused on the self-sustainable oscillations of plant circadian clocks, which can only be observed under artificial constant environmental conditions. However, plants have evolved under natural diurnal conditions where several major environmental cues such as light, temperature and humidity are dramatically changing and interacting with each other. Therefore, little is known about the roles of the plant circadian clock in natural field conditions. Molecular genetic analyses in Arabidopsis thaliana have revealed that some core circadian clock genes are required for the establishment of robust circadian rhythms under artificial diurnal conditions, and that others function only as self-oscillators. However, it is largely unknown yet how those robust rhythms can be obtained under natural diurnal conditions. Recently, an extensive time-course transcriptome analysis of rice (Oryza sativa) leaves in natural field conditions revealed that OsGIGANTEA, the sole rice ortholog of the Arabidopsis GIGANTEA gene, governs the robust diurnal rhythm of rice leaf transcriptomes even under natural diurnal conditions; rice Osgi mutants exhibited severely defective transcriptome rhythms under strong diurnal changes in environmental cues. This review focuses on the physiological significance of the plant circadian clock in natural field conditions.


BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET Inhibitor.
Bromodomain and extra-terminal (BET) family proteins are key regulators of gene expression in cancer. Herein, we utilize BRD4 profiling to identify critical pathways involved in pathogenesis of chronic lymphocytic leukemia (CLL). BRD4 is overexpressed in CLL and is enriched proximal to genes upregulated or de novo expressed in CLL with known functions in disease pathogenesis and progression. These genes, including key members of the B-cell receptor (BCR) signaling pathway, provide a rationale for this therapeutic approach to identify new targets in alternative types of cancer. Additionally, we describe PLX51107, a structurally distinct BET inhibitor with novel in vitro and in vivo pharmacologic properties that emulates or exceeds the efficacy of BCR signaling agents in preclinical models of CLL. Herein, the discovery of the involvement of BRD4 in the core CLL transcriptional program provides a compelling rationale for clinical investigation of PLX51107 as epigenetic therapy in CLL and application of BRD4 profiling in other cancers.Significance: To date, functional studies of BRD4 in CLL are lacking. Through integrated genomic, functional, and pharmacologic analyses, we uncover the existence of BRD4-regulated core CLL transcriptional programs and present preclinical proof-of-concept studies validating BET inhibition as an epigenetic approach to target BCR signaling in CLL. Cancer Discov; 8(4); 458-77. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 371.


The development of an instrument for assessing the quality of life of people with diabetes. Diabetes-39.
The aim of this 2-year research project was to develop an instrument specifically designed to assess the quality of life of people with diabetes. The project was divided into two phases. In the first phase, information from a detailed literature review, from existing quality-of-life instruments, and from interviews with health professionals and people with diabetes was used to develop an initial instrument of 92 items considered to address important aspects of patients' lives. This questionnaire was mailed to 1,000 people with diabetes, and data from the 516 respondents were used to select the most important and useful items. Fifty items were excluded, leaving 42 items that constituted the pilot instrument. During phase 2, the pilot instrument was used to assess the quality of life of 427 diabetic patients who completed the revised questionnaire. After analyzing this data, three additional items were dropped. The final instrument consists of 39 items and covers five dimensions of patients' lives: Energy and Mobility, Diabetes Control, Anxiety and Worry, Social Burden, and Sexual Functioning. The results of validity and reliability tests conducted to date testify to the relevance of the 39-item questionnaire (Diabetes-39) as a valid discriminative instrument, one which shows significant correlations with an overall quality-of-life assessment, the pattern of diabetes severity, and comorbidity. Further, the results from Diabetes-39 correlate well with the results from the established generic quality-of-life instrument, the Medical Outcomes Study 36-Item Short-Form Health Survey. Validation of a quality-of-life instrument, however, is an ongoing process. Further research is required to corroborate these early findings and to ensure that this is an instrument that can capture data of greatest relevance to the diabetic patient and that is responsive to change in quality of life.


From "An Enzyme Able to Destroy Penicillin" to Carbapenemases: 70 Years of Beta-lactamase Misbehaviour.
As early as 1940, Abraham and Chain described "an enzyme able to destroy penicillin". In the late 1940's, penicillin-resistant strains of Staphylococcus aureus were found to be a clinical problem. They produced a penicillinase that could hydrolyze the amide bond in the β-lactam ring. Later, an enzyme mediated by an R-factor was isolated from Enterobacteriaceae. Methicillin and cephalosporins, both very poor substrates of the S. aureus enzyme, were found to be sensitive to this new enzyme. Third generation cephalosporins appeared to solve the problem, but further enzymes were selected that exhibited extended spectra and could for instance hydrolyze cefotaxime and/or ceftazidime. The discovery of carbapenems constituted a major advance for our antimicrobial arsenal: they inactivated most of the essential penicillin binding proteins effectively and escaped the activity of nearly all known -β lactamases. However, the metallo-β-lactamases, which had not been recognised as a major danger before 1990, were found to act as effective carbapenemases and started to spread in a worrying way. Moreover, carbapenem-hydrolyzing enzymes were found in each of the 3 classes of active-site serine β-lactamases.


Rectal transmission of bovine leukemia virus in cattle and sheep.
Bovine leukemia virus (BLV) was transmitted by rectal inoculation of BLV-infective whole blood into cattle and sheep. Two cows and 2 sheep each were given 500 ml and 50 ml of blood, respectively, by rectal infusion. Two sheep which served as positive controls each were given 1 ml of the same blood, IV. All animals became seropositive to BLV by postinoculation week 5. Although relatively large volumes of blood were used for rectal inoculation, a base line for infectivity was established for the rectal route.


Alpha interferon and acyclovir treatment of herpes simplex virus in lymphoid cell cultures.
The T-lymphoblastoid cell line CEM, persistently infected with herpes simplex virus type 1, has been used to examine the antiviral efficacy of human alpha interferon and acyclovir, both alone and in combination. Acyclovir and interferon each produced dose-dependent decreases in virus titer at concentration ranges of 1 to 100 microM (approximately 0.225 to 22.5 micrograms/ml) and 10 to 10,000 U/Ml, respectively. Mean reductions in titer of 1.9 and 4.2 log10 PFU/ml were observed with 100 microM acyclovir and 10,000 U of interferon per ml, respectively, on day 10 of treatment. The combination of 100 microM acyclovir and 10,000 U of interferon per ml produced the most rapid fall in virus titer of all regimens examined and elimination of infections virus by day 7. Prolonged treatment (greater than 10 days) with acyclovir or alpha interferon was accompanied by a gradual return of virus titer to control levels despite the continuous presence of drug. Virus preparations isolated from such cultures were tested for antiviral agent sensitivity by a plaque reduction method. Acyclovir-exposed isolates were found to be acyclovir resistant, with 50% inhibitory doses of greater than 200 microM, and to be thymidine kinase deficient. Alpha interferon-exposed isolates were not interferon resistant. These results suggest that, in persistently herpes simplex virus-infected CEM cells: (i) combination treatment with 100 microM acyclovir and 10,000 U of alpha interferon per ml is more effective in reducing virus titer than either agent alone; (ii) prolonged exposure to drug may result in development of resistance by either the virus strain or the host cell system; and (iii) development of acyclovir resistance by herpes simplex virus in lymphoid cells is mediated by thymidine kinase.


A Sharp Jump in Photocatalytic Activity of Elemental Sulfur for Dye Degradation in Alkaline Solution.
Elemental sulfur is a low-cost and abundant substance as one of the largest by-products of the oil industry which was widely used in many industrial activities. Cyclo-octasulfur (S8 ) is one of the sulfur allotropes that is a very stable substance in standard conditions. In this study, we report a low-cost and fast method for the degradation of methyl violet in water under visible light and also sunlight by using elemental sulfur (S8 ). The results show that sulfur is a good photocatalyst which operates under visible light and can be utilized for degradation of methyl violet. The photocatalytic degradation of methyl violet in acidic, neutral, and alkaline media was investigated, and it was found that the photocatalytic efficiency increases dramatically in alkaline solution. The effects of the initial concentration of the dye, photocatalyst dosage, solution pH, and photocatalyst reusability were investigated. The kinetics of the reaction were studied in detail, and the photocatalytic rate equation was presented.